Preclinical Testing of Integrin Enhancing Molecules for the Treatment of Muscular

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种致命的肌肉萎缩性疾病，目前没有治愈或有效的治疗方法。DMD是由编码肌营养不良蛋白的基因突变引起的，导致肌营养不良蛋白的缺失，肌营养不良蛋白是肌肉中层粘连蛋白结合肌营养不良蛋白糖蛋白复合物的关键组分。肌营养不良蛋白的缺失导致肌膜完整性降低和对肌肉损伤的易感性增加。1721整合素也是肌肉中的主要层粘连蛋白受体，其在DMD患者和mdx小鼠模型中增加。这些观察结果导致了1721整合素是DMD疾病进展的主要调节剂的假设。为了支持这一观点，肌肉中17整合素的转基因过表达加重了营养不良小鼠的肌肉疾病，而营养不良肌肉中17整合素的缺失导致更严重的疾病。这些结果共同表明，促进肌肉中整合素表达增加的药理学干预可能是治疗DMD的有效治疗方法。最近，使用一种新的基于肌细胞的测定和药物发现技术，我们已经确定了几种化合物，增加17整合素在培养的肌细胞中的表达。在这项研究中，我们将在DMD小鼠模型中开始这些化合物的临床前试验。我们的研究将确定这些化合物的最佳剂量，并确定它们是否能延长DMD小鼠模型的寿命并预防肌肉疾病的进展。化合物也将进行测试，以确定他们是否防止发展扩张型心肌病与肌肉萎缩症使用超声心动图，如果他们防止肌肉功能恶化。这些目标将使我们能够检验增加17整合素基因表达的化合物可以预防DMD小鼠模型中肌肉疾病进展的假设。在DMD小鼠模型中识别增加17整合素表达并预防肌肉疾病的化合物将成为未来研究的基础，这些研究将把我们的基础生物医学研究转化为DMD临床试验药物的开发。 公共卫生相关性：杜氏肌营养不良症（DMD）是一种毁灭性的肌肉疾病，影响着美国和欧盟近5万名儿童。17整合素的表达增加已显示在DMD小鼠模型中是非常有益的。本研究的目的是进行临床前试验的新药，提高17整合素在肌肉中的表达，以确定他们是否可能对DMD患者的治疗价值。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease for which there is currently no cure or effective treatment. DMD is caused by mutations in the gene encoding dystrophin resulting in an absence of the dystrophin protein, a critical component of the laminin binding dystrophin glycoprotein complex in muscle. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The 1721 integrin is also a major laminin receptor in muscle that is increased in DMD patients and the mdx mouse model. These observations led to the hypothesis that the 1721 integrin is a major modifier of disease progression in DMD. In support of this idea, transgenic over-expression of the 17 integrin in muscle alleviates muscle disease in dystrophic mice, while loss of 17 integrin in dystrophic muscle results in more severe disease. Together these results indicate pharmacological interventions which promote increased 17 integrin expression in muscle may be an effective therapeutic approach for the treatment of DMD. Recently, using a novel muscle cell-based assay and drug discovery technology, we have identified several compounds that increase 17 integrin expression in cultured muscle cells. In this study we will initiate preclinical testing of these compounds in mouse models of DMD. Our studies will determine the optimal dose of these compounds and determine if they increase longevity and prevent muscle disease progression in DMD mouse models. Compounds will also be tested to determine if they prevent the development of dilated cardiomyopathy associated with muscular dystrophy using echocardiography and if they prevent deterioration in muscle function. Together these aims will allow us to test the hypothesis that compounds which increase 17 integrin gene expression can prevent muscle disease progression in mouse models of DMD. The identification of compounds that increase 17 integrin expression and prevent muscle disease in mouse models of DMD will form the basis of future studies that will translate our basic biomedical research into the development of drugs for clinical trials for DMD. PUBLIC HEALTH RELEVANCE: Duchenne Muscular Dystrophy (DMD) is a devastating muscle disease that affects nearly 50,000 children in the United States and European Union. Increased expression of 17 integrin has been shown to be enormously beneficial in DMD mouse models. This study aims to conduct preclinical testing of novel drugs that enhanced 17 integrin expression in muscle to determine if they maybe of therapeutic value to DMD patients.